Abstract

The mRNA is co-transcriptionally bound by a number of RNA-binding proteins (RBPs) that contribute to its processing and formation of an export-competent messenger ribonucleoprotein particle (mRNP). In the last few years, increasing evidence suggests that RBPs play a key role in preventing transcription-associated genome instability. Part of this instability is mediated by the accumulation of co-transcriptional R loops, which may impair replication fork (RF) progression due to collisions between transcription and replication machineries. In addition, some RBPs have been implicated in DNA repair and/or the DNA damage response (DDR). Recently, the Npl3 protein, one of the most abundant heterogeneous nuclear ribonucleoproteins (hnRNPs) in yeast, has been shown to prevent transcription-associated genome instability and accumulation of RF obstacles, partially associated with R-loop formation. Interestingly, Npl3 seems to have additional functions in DNA repair, and npl3∆ mutants are highly sensitive to genotoxic agents, such as the antitumor drug trabectedin. Here we discuss the role of Npl3 in particular, and RBPs in general, in the connection of transcription with replication and genome instability, and its effect on the DDR.

Figure 2. Model illustrating the role of Npl3 coupling mRNP biogenesis and export. In wild-type cells (top), the mRNA is properly assembled into an export-competent mRNP with the collaboration of RNA-binding factors such as Npl3, THO/TREX, Nab2, and Mex67-Mtr2. This facilitates RF progression through transcribed DNA regions. However, in npl3∆ cells (bottom) the mRNA packaging is defective, and the nascent mRNA may hybridize with the transcribed DNA strand, leading to R loops that favor the accessibility of DNA damaging agents to the non-transcribed single-stranded DNA and that constitute an obstacle for RF progression. Antitumor drug trabectedin (ET-743) might act similarly to an R loop.